Abnormal metabolism is a hallmark of cancer. Mitochondria are semiautonomous organelles within cells that play an essential role in cellular energy metabolism, free radical generation, and apoptosis. They are also the primary source of generating reactive oxygen species. Our mechanism-based mathematical model of cancer metabolism suggests that aggressively metastatic tumors maintain a hybrid metabolic phenotype for their metabolic plasticity and survival advantage. Therapeutic approaches to abolish the hybrid metabolic state are important for enhancing their response to anticancer therapy and preventing metastasis. Triple-negative breast cancer (TNBC) has a high energy dependency on mitochondrial fatty acid beta-oxidation (FAO). FAO activates c-Src, one of the frequently upregulated oncopathways in TNBC. Biguanides such as metformin are the most widely administered anti-diabetic agents and are recently indicated for cancer therapy. However, multiple clinical trials reported limited in vivo anticancer response for metformin as a single agent. Biguanides can suppress OXPHOS by inhibiting the complex-I activity of the mitochondrial electron transport chain. However, biguanides are also an activator of the energy sensor AMPK, an upstream of FAO. Thus, biguanides can play opposing roles in mitochondrial metabolism, especially in FAO-dependent tumors. We analyzed the significance of these opposing roles of biguanides in TNBC metabolism and oncopathway activation. In vivo studies suggested that the tumor bioavailability of biguanides is critical for its antitumor activity, especially in FAO-dependent tumors like TNBC. Combining metformin with FAO or its target inhibitors significantly improved the antitumor activity compared to the single drug therapy. To conclude, metabolic targeting of TNBC requires a suitable combination approach to overcome resistance development from metabolic crosstalk.

Dr. Kaipparettu is an Associate Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine, Houston, USA. His research team focuses on the role of mitochondrial metabolism and mitochondria-nuclear crosstalk in cancer.